<scp>TACI</scp> variants as underlying condition in autoimmune neutropenia: Description of four cases
Authors: Francesca Fioredda, Andrea Beccaria, Elena Turrini, Pietro Casartelli, Domenico Coviello, Massimo Maffei, Marina Lanciotti, Michela Lupia, Paola Terranova, Alice Grossi, Isabella Ceccherini, Maurizio Miano, Carlo Dufour
Journal: American Journal of Hematology (2022)

Dr Bergman and colleagues have recently described a case of refractory autoimmune neutropenia (AINP) in a patient carrying the p.A181E (NM_012452) variant of the TACI gene.1 The patient had a very severe clinical manifestation, including AINP refractory to granulocyte colony-stimulating factor (G-CSF), which was complicated by pure red cell aplasia (PRCA). The authors have highlighted the rarity of the association between an apparent acquired disorder (AINP) and an inherited condition of immune dysregulation.1 The transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a member of the tumor necrosis factor receptor superfamily (TNF(R)SF), promotes T-cell-independent antibody responses and plasma cell differentiation and counteracts BAFF-driven B cells. Defects in TNF(R)SF members were first described in common variable immune deficiency and selective immunoglobulin A deficiency, but the spectrum of disorders attributed to TNF(R)SF has widened, involving benign lymphoproliferation and an increased autoimmunity rate.2 Abnormal TACI signaling is frequently related to autoimmune "signature," as shown by the tendency to develop autoimmune cytopenia, which is 3.34-fold higher in patients with TACI mutation than that in the healthy population.2, 3 Increasing evidence suggests that some autoimmune disorders, including cytopenia, represent an early sign of primary immune dysregulation disorders (PIRD). In pediatric patients, a subgroup of inborn errors of immunity, recently named PIRD, has been shown to play a relevant role in the development of autoimmune cytopenia, which is characterized by abnormal functioning of the immune system without severe immunodeficiency, lymphoproliferation, autoimmune disorders, and predisposition to malignancies.4, 5 In the case of an attenuated clinical phenotype, these disorders may be easily underestimated, particularly in adults.6 However, in pediatric patients, AINP or other mono-/multi-lineage autoimmune cytopenias appear to be epiphenomena of immunedysregulation.7 For example, cytopenia can be caused by impaired marrow cell production, as observed in aplastic anemia (AA) and PRCA, or increased destruction of peripheral blood cells, as seen in Evans' syndrome.8, 9 The case reported by Bergman gives us an opportunity to share the experience of the Pediatric Hematology Unit of the IRCCS, G. Gaslini Research Hospital on autoimmune/idiopathic neutropenia, which was initially considered an acquired disorder but was eventually shown to be an immune dysregulation associated with TACI variants. From 2012 to 2022, 58 patients affected by chronic AINP underwent complete workup, including a dedicated genetic panel. Four of them (one female) were found to have mutated TACI variants. The median age at first observation was 109 months (range, 108–144 months). All patients were in good clinical condition after a follow-up of 30 months (range, 20–90 months) and are currently being followed up at a median age of 174 months (range, 156–324 months). Data were collected according to the Italian Neutropenia Registry (INR) rules approved by the local ethics committee. Three of four patients had "classical" AINP with positivity for indirect anti-neutrophil antibody. Patient 2 tested negative on the indirect anti-neutrophil antibody test using two consecutive samples. Therefore, according to the INR definition, the patient was considered to have "idiopathic neutropenia." Given the low sensitivity of the method used (indirect antibodies tests by GIFT), Patient 2 could have been diagnosed with classical AINP on repeat testing.10 All patients presented with mild or moderate clinical phenotypes. In Patient 2, osteomyelitis in the absence of immunoglobulin depletion or other immunodeficiency features was the reason for the first hospital admission. Patients 3 and 4 had a history of mild recurrence of upper respiratory tract infections and diarrhea during early infancy (Table 1). Neutropenia was mild in all patients, except in Patient 1, who had severe neutropenia (0.44 × 103/μl). Leukopenia was present in all patients since the beginning of their clinical history (median white blood cell count: 3.17 × 103/μl, range, 1.84–3.83 × 103/μl) and was associated with borderline low lymphocyte count in Patient 1. No association with thrombocytopenia or hemolytic anemia was observed over time. G-CSF and other immunosuppressants were never administered. No association with other signs or biomarkers of autoimmunity or subsequent appearance of other cytopenias has been observed in this cohort to date. The immunological pattern of our cohort did not show the expected exhaustion of immunoglobulins; however, lower levels of absolute B cell count were observed in two of four patients. In the three patients in whom B cell subpopulations were studied, the number of marginal zone cells (CD27+IgD+IgM+) was increased compared to reference values, while the number of switched memory cells (CD27+IgD−IgM−) and memory B cells were below the normal range. The number of double-negative (DN) B cells (CD27−IgD−) was increased compared to normal values in two of three patients. The number of CD4+ and CD8+ T cells was normal, whereas that of T regs (CD3+CD4+ CD25bright+) was reduced in three of four patients (Table 1). In patients who underwent bone marrow, maturation was normal with no block at the promyelocyte stage. Cytogenetic abnormalities were not observed. Genetic analysis using an NGS panel including 161 genes involved in immunodeficiency/immunedysregulations, autoimmune disorders, and marrow failures showed that Patients 1, 2, and 3 had heterozygous pathogenic variants (p.Cys193Ter, p.Ile87Asn, and p.Trp40 Arg, respectively), previously described as risk-increasing TNFRSF13B variants in antibody deficiency syndromes,3 while Patient 4 had the same variant p.Ala181Glu as that reported in Bergman et al.'s case (Table 1). Overall, our cohort presented with isolated neutropenia with no additional autoimmune markers, mild-to-moderate infection profile (the right ischial branch osteomyelitis of Patient 2 resolved completely after the standard long-term prolonged antibiotic treatment with no recurrence), no substantial limitations of the quality of life, lack of immunoglobulin exhaustion typical of TACI disease but consistent with the young age of the cohort, tendency to have fewer B cells, abnormal switched B cells, and memory B cell depletion, as reported in patients with TACI mutations.1, 2 Pathogenic variants of TACI have incomplete penetrance and variable expression. The presence of a homozygous or heterozygous variant, the possible role of additional genetic variants, or exposure to environmental factors (i.e., microbial exposure) could be responsible for this heterogeneity1, 2 and the wide spectrum of clinical features ranging from severe to silent/mild phenotypes.1, 2 It is important to highlight the presentation of TACI disorders with mild symptomatic neutropenia that may further evolve in the long term to severe/refractory mono-/multi-lineage cytopenia, as shown by the case report by Bergman et al.1 Even if the patient reported by Dr Bergman et al.1 in good clinical condition up to adulthood, he might have carried some asymptomatic immunological disturbance long before his first admission, consistent with the long time required for the progressive exhaustion of cellular reserves, typical of the natural history of TACI disease. Differentiating TACI-related neutropenia from a typical primary autoimmune dysfunction may be challenging in infancy.10 Factors such as older age of presentation, longer duration of neutropenia, leukopenia, and lymphopenia could be signs, as we already described, of "atypical" AINPs.7 Moreover, a reduced number of total B cells, B switched cells, and B memory cells with an increase in the number of DN B cells should raise the suspicion of an underlying immune dysregulation. In particular, an increase in DN B cells has been described in several autoimmune disorders (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, neuromyelitis optica, myasthenia gravis, and Guillain–Barré syndrome); however, their role in these diseases is unclear. One hypothesis (also seen in a vaccination response model) is that DN B cells may represent a source of disease-relevant immunoglobulins.11 These four cases together with the one described by Bergman et al. highlight that autoimmune cytopenias that show nontypical features or those that are refractory to common therapies require special immunologic and genetic investigation. In our patients, the identification of pathogenic mutations in TACI, one of the most common drivers of PIRD (but not the unique) suggests that the mechanism of neutropenia is likely sustained by dysregulation of the central B cell tolerance with missing self-antigen recognition. In these particular cases tailored follow-up including strict monitoring of immunoglobulin levels/lymphocyte subsets to document any immune cell exhaustion and the clinical surveillance for the appearance of autoimmune signs/surrogate markers is highly recommended. Early recognition of the type of AINP is critical to offer the best monitoring program and optimal therapy possibly tailored to the underlying disorder (i.e., immunoglobulin replacement), particularly in light of severe clinical findings such as PRCA, which may appear over the course of the disease. This specific type of evolution, as indicated by recent findings from our group,8, 9 outlines the need to investigate the underlying PID/PIRD in childhood marrow failure. Finally, the occurrence of PID/PIRD-related neutropenia in late childhood/young adulthood highlights the importance of establishing good collaborations between pediatricians and hematologists to share diagnostic algorithms and treatment protocols. The authors acknowledge Editage for the editorial revision of the paperand Dr Elena Ricolfi for secretarial assistance. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.